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DMO03 CEP290 mutations are a frequent cause of Joubert syndrome with oculo-renal involvement
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Abstracts: Oral Presentations, Seventh European Paediatric Neurology Society (EPNS) Congress
congenital brain malformations. Detailed documentation of MCD-patients with a suspected, but unconfirmed, genetic cause, will provide opportunities to guide the search for more genes involved in brain developmental disorders. DMO02 The Lis-1 gene mutations are manifested as different types of cortical malformations 2 , J. Galant1 . F. Carratala´ 1 *, S. Mart´ınez2 , P. Andreo1 , T. Escamez ´ 1 San Juan de Alicante University Hospital, 2 Neuroscience Institute of Alicante, Alicante, Spain
Background: Phenotypic expressions of Lis-1 gene mutations are in the base of many CNS malformations such as MillerDieker syndrome, and also in less specific ones. Aim: To determine the presence of Lis-1 sequence mutations among patients suffering from different CNS structural anomalies. Patients and Interventions: Out of ten patients with abnormal MRI scans (two girls and eight boys), five suffered from epilepsy, four from developmental delay and one was affected by the Walker-Valburg syndrome. Genomic sequence analyses for Lis-1 microsatellites (EST001616, WII5114, RH12602, and D17S1267) were performed. Case
Lis-1 mutation
MRI
Symptoms
1 (female) 2 (male)
D17S1866 del. D17S1866 del.
Pachygyria Cortical dysplasia
3 (male) 4 (male)
D17S5 ins. D17S5 ins.
Cortical dysplasia Cerebral hemiatrophy
5 (female) 6 (male)
Normal D17S79−2 ins.
Pachygyria Cobblestone complex
7 (male) 8 (male) 9 (male) 10 (male)
D17S79−2 ins. Normal Normal D17S18866 ins.
Hypomyelinization Cortical dysplasia Cerebral hemiatrophy Cortical dysplasia
Microcephalus Partial epilepsy, hemiplejia Monoparesis Neurodevelopmental delay Partial Epilepsy Walker-Warburg Synd. Myoclonic epilepsy Status epilepticus Plagiocephaly Partial Epilepsy
Conclusions: 1) There is a high prevalence of Lis-1 mutations among the studied patients. 2) There is a wide variety of phenotypic expressions in Lis-1 mutations. DMO03 CEP290 mutations are a frequent cause of Joubert syndrome with oculo-renal involvement E.M. Valente1 *, F. Brancati2 , G. Barrano7 , J.L. Silhavy3 , S.E. Marsh3 , E. Bertini5 , E. Boltshauser6 , B. Dallapiccola7 , J.G. Gleeson3 . 1 IRCCS CSS, Mendel Institute, Rome, and Dept. of Medical and Surgical Paediatric Sciences, University of Messina, Messina, 2 IRCCS CSS, Mendel Institute, Rome, and CeSI, Aging Research Centre, Dept. of Biomedical Sciences, G. d’Annunzio University Foundation, Chieti, Italy, 3 Neurogenetics Laboratory, Department of Neurosciences, 4 Neurogenetics Laboratory, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA, 5 Molecular Medicine Unit, Department of Laboratory Medicine, IRCCS Bambino Gesu` Hospital, Rome, Italy, 6 Department of Neurology, Children’s University Hospital, Zurich, Switzerland, 7 IRCCS CSS, Mendel Institute, Rome, and Dept. of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy Background: Joubert syndrome related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions characterized by variable multiorgan involvement, mainly of the central nervous system, eyes and kidneys, and sharing a peculiar midbrain-hindbrain malformation (the Molar Tooth Sign). There is clinical and genetic overlap between JSRDs and other pleiotropic disorders such as Meckel (MKS), SeniorLoken (SLS) and Bardet Biedl syndromes. Functional studies on the underlying causative genes have demonstrated a
common pathogenetic mechanism related to the dysfunction of the primary cilium. Mutations in the CEP290 gene were recently identified in JSRD families with oculo-renal involvement typical of SLS, as well as in patients with isolated Leber Congenital Amaurosis and with MKS. Purpose: To assess the frequency and phenotypic spectrum of CEP290 mutations in JSRD. Methods: CEP290 mutation analysis was performed on 128 JSRD patients by DHPLC and direct sequencing of abnormal elution patterns. Results and discussion: We identified mutations in 19/44 patients with a cerebello-oculo-renal phenotype and in 2/84 patients representing the spectrum of the other JSRD subtypes. The data suggest that, among JSRDs, CEP290 mutations are frequent and largely specific to the cerebellooculo-renal phenotype. One mutated patient displayed situs inversus, a condition also found in other ciliopathies. DMO04 Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance P.G. Barth1 , C.B. Majoie2 , M.W.A. Caan2 , M.A.J. Weterman2 , M. Kyllerman3 , L.S. Smit4 , R.A. Kaplan5 , R.H. Haas6 , F. Baas2 , J.-M. Cobben1 , B.T. Poll-The1 *. 1 Emma Children’s Hospital, 2 Academic Medical Center, Amsterdam The Netherlands, 3The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Goteborg, Sweden, 4 Free University Hospital, Amsterdam, The Netherlands, 5 Kaiser Permanente Hospital, San Diego, 6 University of California San Diego la Jolla, USA Four unrelated children presented with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction, and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), unilateral facial palsy (2/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with color coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name “pontine tegmental cap dysplasia” (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI. DMO05 Spinal and muscular histology in fetal spina bifida D. Sival *, O. Brouwer, K. Sollie, R. Verbeek, A. Bos, W. den Dunnen. University Medical Center Groningen, University of Groningen, the Netherlands Background: In spina bifida aperta (SBA), leg movements caudal to the meningomyelocele (MMC) are present in utero, but they disappear shortly after birth. Insight in underlying pathophysiology is relevant for the development of therapeutic strategies. In fetal SBA, we investigated neuromuscular histology to determine the cause for movement loss. Patients and Methods: We analyzed neuromuscular histology of SBA fetuses (n = 8; 16−40 weeks gestational age) with MMC at cervical (n = 1), thoracic (n = 5) or lumbar (n = 2) level. Histology of spinal segments (n = 8) and myotomes
Abstracts: Oral Presentations, Seventh European Paediatric Neurology Society (EPNS) Congress
congenital brain malformations. Detailed documentation of MCD-patients with a suspected, but unconfirmed, genetic cause, will provide opportunities to guide the search for more genes involved in brain developmental disorders. DMO02 The Lis-1 gene mutations are manifested as different types of cortical malformations 2 , J. Galant1 . F. Carratala´ 1 *, S. Mart´ınez2 , P. Andreo1 , T. Escamez ´ 1 San Juan de Alicante University Hospital, 2 Neuroscience Institute of Alicante, Alicante, Spain
Background: Phenotypic expressions of Lis-1 gene mutations are in the base of many CNS malformations such as MillerDieker syndrome, and also in less specific ones. Aim: To determine the presence of Lis-1 sequence mutations among patients suffering from different CNS structural anomalies. Patients and Interventions: Out of ten patients with abnormal MRI scans (two girls and eight boys), five suffered from epilepsy, four from developmental delay and one was affected by the Walker-Valburg syndrome. Genomic sequence analyses for Lis-1 microsatellites (EST001616, WII5114, RH12602, and D17S1267) were performed. Case
Lis-1 mutation
MRI
Symptoms
1 (female) 2 (male)
D17S1866 del. D17S1866 del.
Pachygyria Cortical dysplasia
3 (male) 4 (male)
D17S5 ins. D17S5 ins.
Cortical dysplasia Cerebral hemiatrophy
5 (female) 6 (male)
Normal D17S79−2 ins.
Pachygyria Cobblestone complex
7 (male) 8 (male) 9 (male) 10 (male)
D17S79−2 ins. Normal Normal D17S18866 ins.
Hypomyelinization Cortical dysplasia Cerebral hemiatrophy Cortical dysplasia
Microcephalus Partial epilepsy, hemiplejia Monoparesis Neurodevelopmental delay Partial Epilepsy Walker-Warburg Synd. Myoclonic epilepsy Status epilepticus Plagiocephaly Partial Epilepsy
Conclusions: 1) There is a high prevalence of Lis-1 mutations among the studied patients. 2) There is a wide variety of phenotypic expressions in Lis-1 mutations. DMO03 CEP290 mutations are a frequent cause of Joubert syndrome with oculo-renal involvement E.M. Valente1 *, F. Brancati2 , G. Barrano7 , J.L. Silhavy3 , S.E. Marsh3 , E. Bertini5 , E. Boltshauser6 , B. Dallapiccola7 , J.G. Gleeson3 . 1 IRCCS CSS, Mendel Institute, Rome, and Dept. of Medical and Surgical Paediatric Sciences, University of Messina, Messina, 2 IRCCS CSS, Mendel Institute, Rome, and CeSI, Aging Research Centre, Dept. of Biomedical Sciences, G. d’Annunzio University Foundation, Chieti, Italy, 3 Neurogenetics Laboratory, Department of Neurosciences, 4 Neurogenetics Laboratory, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA, 5 Molecular Medicine Unit, Department of Laboratory Medicine, IRCCS Bambino Gesu` Hospital, Rome, Italy, 6 Department of Neurology, Children’s University Hospital, Zurich, Switzerland, 7 IRCCS CSS, Mendel Institute, Rome, and Dept. of Experimental Medicine and Pathology, La Sapienza University, Rome, Italy Background: Joubert syndrome related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions characterized by variable multiorgan involvement, mainly of the central nervous system, eyes and kidneys, and sharing a peculiar midbrain-hindbrain malformation (the Molar Tooth Sign). There is clinical and genetic overlap between JSRDs and other pleiotropic disorders such as Meckel (MKS), SeniorLoken (SLS) and Bardet Biedl syndromes. Functional studies on the underlying causative genes have demonstrated a
common pathogenetic mechanism related to the dysfunction of the primary cilium. Mutations in the CEP290 gene were recently identified in JSRD families with oculo-renal involvement typical of SLS, as well as in patients with isolated Leber Congenital Amaurosis and with MKS. Purpose: To assess the frequency and phenotypic spectrum of CEP290 mutations in JSRD. Methods: CEP290 mutation analysis was performed on 128 JSRD patients by DHPLC and direct sequencing of abnormal elution patterns. Results and discussion: We identified mutations in 19/44 patients with a cerebello-oculo-renal phenotype and in 2/84 patients representing the spectrum of the other JSRD subtypes. The data suggest that, among JSRDs, CEP290 mutations are frequent and largely specific to the cerebellooculo-renal phenotype. One mutated patient displayed situs inversus, a condition also found in other ciliopathies. DMO04 Pontine tegmental cap dysplasia: a novel brain malformation with a defect in axonal guidance P.G. Barth1 , C.B. Majoie2 , M.W.A. Caan2 , M.A.J. Weterman2 , M. Kyllerman3 , L.S. Smit4 , R.A. Kaplan5 , R.H. Haas6 , F. Baas2 , J.-M. Cobben1 , B.T. Poll-The1 *. 1 Emma Children’s Hospital, 2 Academic Medical Center, Amsterdam The Netherlands, 3The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Goteborg, Sweden, 4 Free University Hospital, Amsterdam, The Netherlands, 5 Kaiser Permanente Hospital, San Diego, 6 University of California San Diego la Jolla, USA Four unrelated children presented with an identical brainstem and cerebellar malformation on MRI. The key findings are: vermal hypoplasia, subtotal absence of middle cerebellar peduncles, flattened ventral pons, vaulted pontine tegmentum, molar tooth aspect of the pontomesencephalic junction, and absent inferior olivary prominence. Peripheral hearing impairment is present in all. Variable findings are: horizontal gaze palsy (1/4), impaired swallowing (2/4), unilateral facial palsy (2/4), bilateral sensory trigeminal nerve involvement (1/4), ataxia (2/4). Bony vertebral anomalies are found in 3/4. Additional MR studies in one patient using diffusion tensor imaging (DTI) with color coding and fibre tracking revealed an ectopic transverse fibre bundle at the site of the pontine tegmentum and complete absence of transverse fibres in the ventral pons. The combined findings indicate an embryonic defect in axonal growth and guidance. Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients. No pathogenic mutations were found. For the purpose of description the name “pontine tegmental cap dysplasia” (PTCD) is proposed for the present malformation, referring to its most distinguishing feature on routine MRI. DMO05 Spinal and muscular histology in fetal spina bifida D. Sival *, O. Brouwer, K. Sollie, R. Verbeek, A. Bos, W. den Dunnen. University Medical Center Groningen, University of Groningen, the Netherlands Background: In spina bifida aperta (SBA), leg movements caudal to the meningomyelocele (MMC) are present in utero, but they disappear shortly after birth. Insight in underlying pathophysiology is relevant for the development of therapeutic strategies. In fetal SBA, we investigated neuromuscular histology to determine the cause for movement loss. Patients and Methods: We analyzed neuromuscular histology of SBA fetuses (n = 8; 16−40 weeks gestational age) with MMC at cervical (n = 1), thoracic (n = 5) or lumbar (n = 2) level. Histology of spinal segments (n = 8) and myotomes